Ceramide (Cer) is involved in regulation of anti-proliferative and apoptotic responses in various cancer cells (Hannun and Obeid, Journal of Biological Chemistry 2002, 277, 25847; Ogretmen and Hannun, Nature Reviews Cancer 2004, 4, 604). In the sphingolipid metabolism cascade, Cer can be formed from the hydrolysis of sphingomyelin (SM), catalyzed by acid and neutral sphingomyelinase (SMase), or synthesized de novo from serine and palmitoyl-CoA (Perry et al., Journal of Biological Chemistry 2000, 275, 9078). Reciprocally, Cer levels can be decreased by conversion into other interconnected bioactive sphingolipid species, which in turn reduces the apoptotic effectiveness of Cer. Cer can be broken down by one of many ceramidases (CDase), leading to the formation of sphingosine (SP). SP is then either acylated back to Cer via Ceramide synthase (CS) or phosphorylated to S1P by sphingosine kinase (SK), of which there are two isoforms, SK1 and SK2 (Hannun and Obeid, Nat Rev Mol Cell Biol 2008, 9, 139). According to the Cer-SP-S1P rheostat model, both Cer and sphingosine are apoptosis-induced lipids, whereas S1P leads to cell proliferation and inflammation and is referred to as a tumor-promoting lipid (Pyne and Pyne, Nat Rev Cancer 2010, 10, 489; Spiegel and Milstien, Nat Rev Mol Cell Bio 2003, 4, 397; Milstien and Spiegel, Cancer Cell 2006, 9, 148; Wymann and Schneiter, Nat Rev Mol Cell Biol 2008, 9, 162). Cer can also be phosphorylated into ceramide 1-phospate (Cer1P) by ceramide kinase (CK), antagonizing the pro-apoptotic action of ceramide and promoting inflammation (Wymann and Schneiter, Nat Rev Mol Cell Biol 2008, 9, 162), or glycosylated to glucosylceramide (GluCer) mediated by glucosylceramide synthase (GCS). The latter results in the development of multidrug resistance in many cancer cells (Ogretmen and Hannun, Nature Reviews Cancer 2004, 4, 604; Reynolds et al., Cancer Letters 2004, 206, 169).
Different strategies have been developed to enhance the level of Cer. For example, many anticancer drugs and stress-induced agonists have been used to increase endogenous Cer levels through de novo synthesis of Cer or the hydrolysis of SM. In addition, treating cancer cells in vitro with more easily dispersed short-chain Cers (C2 to C8-Cer) almost always produces apoptosis and cell-cycle arrest, and those exogenous Cers compete metabolically with natural Cers and their metabolites (Radin, Biochem J 2003, 371, 243). Currently, a number of anticancer agents in clinical trials act to increase Cer levels via inhibition of the conversion of GluCer and Cer1P from Cer, or by blocking the hydrolysis of Cer to S1P (Radin, Biochem J 2003, 371, 243). Sphingosine analogs that serve as pharmacological inhibitors of SK have been developed, including DMS (N,N-dimethylsphingosine) (Edsall et al., Biochemistry-Us 1998, 37, 12892; Yatomi et al., Biochemistry-Us 1996, 35, 626) and sphingamine (D, L-threo-dihydrosphingosine) (Ahn et al., Experimental Biology and Medicine 2006, 231, 1664; Ahn and Schroeder, Anticancer Res 2010, 30, 2881). FTY720 (fingolimod) has also been known to directly inhibit SK1 activity, reduce tumor metastasis and increase apoptosis (Lim et al., Journal of Biological Chemistry 2011, 286, 18633). In addition, aromatic sphingosine analogs have been assessed as stronger sphingosine kinase inhibitors (Murakami et al., Bioorg Med Chem Lett 2005, 15, 1115; Moreno et al., Organic Letters 2011, 13, 5184; Lim et al., Bioorg Med Chem Lett 2004, 14, 2499). For example, water soluble sphingosine analog BML-258 (FIG. 1) is an SK1 selective inhibitor and is efficacious both in vitro and in vivo (Paugh et al., Blood 2008, 112, 1382; Pyne et al., Cancer research 2011, 71, 6576).
Accordingly, disclosed herein are synthetic methods and compounds related to the synthesis of bioactive compounds. The synthetic methods and compounds provide useful routes and efficient synthesis of the enantiomers of sphingosine derivatives with high diastereomeric excess.